Chronic obstructive pulmonary disease (COPD), encompassing chronic bronchitis with or without emphysema, is currently the seventh leading cause of death in Taiwan and the third leading cause of death in the United States. Worldwide COPD morbidity and mortality are expected to increase dramatically in the next ten years. Although cigarette smoking is the primary risk factor for COPD, not all smokers are equally likely to develop COPD in their lifetimes. It is suggested that genetics also plays an important role in the development of COPD. (Sandford A J, Silverman E K. Chronic obstructive pulmonary disease (Susceptibility factors for COPD the genotype-environment interaction. Thorax 2002; 57: 736-741); and identifying genetic determinants and investigating their functions may lead to beneficial progress in understanding COPD pathobiology, diagnosis, and treatment (Sandford A J, Silverman E K. Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD the genotype-environment interaction. Thorax 2002; 57: 736-741).
Surfactant protein-D (SP-D), which lines the alveolar epithelium, is synthesized in type II pneumocytes and Clara cells as a large multimeric, calcium binding hydrophilic protein (Kishore U, Greenhough T J, Waters P, Shrive A K, Ghai R, Kamran M F, Bernal A L, Reid K B, Madan T, Chakraborty T. Surfactant proteins SP-A and SP-D: structure, function and receptors. Mol Immunol 2006; 43: 1293-1315). SP-D, as an innate immunity molecule, plays an important role in host defense and regulation of inflammation, which are essential factors in the pathogenesis of asthma (Wang J Y, Reid K B M. The immunoregulatory roles of pulmonary surfactant protein A and D in allergic inflammation of asthma. Immunobiol 2007; 212: 417-425), lung injury (Aono Y, Ledford J G, Mukherjee S, Ogawa H, Nishioka Y, Sone S, Beers M F, Noble P W, Wright J R. Surfactant protein-D regulates effector cell function and fibrotic lung remodeling in response to bleomycin injury. Am J Respir Crit Care Med 2012; 185: 525-536), and COPD (Hartl D, Griese M. Surfactant protein D in human lung diseases. Eur J Clin Invest 2006; 36: 423-435.). Several studies also found genetic variants of the SFTPD gene were associated with serum concentrations of SP-D.
SP-D is thought to play an significant role in the pathogenesis of COPD by reducing oxidant production (Groves A M, Gow A J, Massa C B, Laskin J D, Laskin D L. Prolonged injury and altered lung function after ozone inhalation in mice with chronic lung inflammation. Am J Respir Cell Mol Biol 2012; 47: 776-783), inflammatory responses in alveolar macrophages (Liu C F, Chen Y L, Chang W T, Shieh C C, Yu C K, Reid K B, Wang J Y. Mite allergen induces nitric oxide production in alveolar macrophages via the CD14/TLR4 complex, and is inhibited by surfactant protein D. Clin Exp Allergy 2005; 35: 1615-1624), and increasing apoptotic cell clearance (Jäkel A, Clark H, Reid K B, Sim R B. The human lung surfactant proteins A (SP-A) and D (SP-D) interact with apoptotic target cells by different binding mechanisms. Immunobiology 2010; 215: 551-558). In known animal studies, increased oxidant production and reactive oxygen species are noted in the lungs of SP-D−/− mice (Yoshida M, Korfhagen T R, Whitsett J A. Surfactant protein D regulates NF-B and Matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways. J Immunol 2001; 166: 7514-7519). Furthermore, mice that lack SP-D develop chronic inflammation and emphysema that can be prevented by administration of truncated recombinant human SP-D (Knudsen L, Ochs M, Mackay R, Townsend P, Deb R, Muhlfeld C, Richter J, Gilbert F, Hawgood S, Reid K, Clark H. Truncated recombinant human SP-D attenuates emphysema and type II cell changes in SP-D deficient mice. Respir Res 2007; 8: 70-76). In fact, a higher level of serum SP-D is suggested as a biomarker associated with COPD risk (Celli B R, Locantore N, Yates J, Tal-Singer R, Miller B E, Bakke P, Calverley P, Coxson H, Crim C, Edwards L D, Lomas D A, Duvoix A, MacNee W, Rennard S, Silverman E, Vestbo J, Wouters E, Agusti A; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185: 1065-1072; Sin D D, Leung R, Gan W Q, Man S P. Circulating surfactant protein D as a potential lung-specific biomarker of health outcomes in COPD: a pilot study. BMC Pulm Med 2007; 7: 13). Foreman and colleagues demonstrated that certain genetic variants of SP-D are associated with changes in serum concentrations of SP-D and lung function, suggesting that SP-D is involved in the pathogenesis of COPD (Foreman M G, Kong X, DeMeo D L, Pillai S G, Hersh C P, Bakke P, Gulsvik A, Lomas D A, Litonjua A A, Shapiro S D, Tal-Singer R, Silverman E K. Polymorphisms in surfactant protein-D are associated with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2011; 44: 316-322). Genetic associations of SP-D with COPD were first investigated early in 2001 and focused mainly on a Mexican population (Guo X, Lin H M, Lin Z, Montario M, Sansores R, Wang G, DiAngelo S, Pardo A, Selman M, Floros J. Surfactant protein gene A, B, and D marker alleles in chronic obstructive pulmonary disease of a Mexican population. Eur Respir J 2001; 18: 482-490). Van Diemen et al showed that the rs2243639 (Thr160A1a) SFTPD SNP was associated with FEV1/inspiratory vital capacity (Van Diemen C C, Postma D S, Aulchenko Y S, Snijders P J, Oostra B A, Van Duijn C M, Boezen H M. Novel strategy to identify genetic risk factors for COPD severity: a genetic isolate. Eur Respir J 2010; 35: 768-775). However, they did not encompass the whole block of the SFTPD gene and only picked up two loci, rs721917 (Met11Thr) and rs2243639 (Thr160Ala), as risk targets Kim et al from the genome-wide association analysis suggested SP-D as serum biomarker as well as a genetic susceptibility marker of COPD (Kim D K, Cho M H, Hersh C P, Lomas D A, Miller B E, Kong X, Bakke P, Gulsvik A, Agusti A, Wouters E, Celli B, Coxson H, Vestbo J, MacNee W, Yates J C, Rennard S, Litonjua A, Qiu W, Beaty T H, Crapo J D, Riley J H, Tal-Singer R, Silverman E K, ECLIPSE, ICGN and COPD Gene Investigators. Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 1238-1247). As mentioned above, although genetic association studies highly suggest that the SFTPD gene contributes to the development of COPD, little comprehensive work has been done regarding the relationship between polymorphisms of the SFTPD gene and COPD-related phenotypes and disease outcomes.